G-protein coupled receptors (GPCRs) are integral membrane proteins at the cell surface that serve as a major communication interface. Encoded by more than 800 genes in the human genome, GPCRs control key physiological functions including neurotransmission, hormone release and blood pressure regulation. GPCRs elicit these physiological functions by signaling through intracellular G proteins when activated by extracellular ligands. Understanding the molecular mechanisms of ligand-mediated GPCR activation and G protein binding has profound implications for modulating cellular signaling. My talk will focus on our efforts in gaining mechanistic insights into the activation and signaling of different families of GPCRs. Specifically, I will present structural and biophysical data on representative Family A (Cannabinoid receptor 1,  b₂-adrenergic receptor) and Family B (Glucagon receptor) and Family C (metabotropic Glutamate receptor5, mGlu5) GPCRs and how similarities and differences in their activation mechanism affect G protein interaction and signaling.